{62 - Ketoacyl derivatives of 6-aminopenicillanic acid and process thereof

ABSTRACT

Beta -Ketoacyl derivatives of 6-aminopenicillanic acid of the formula:   ARE DISCLOSED. In the above structure R1 is hydrogen, alkyl, halogen, alkoxy, cyano, trifluoromethyl and the like; Z is CHR2 or NR2; R2 is hydrogen, alkyl, aralkyl; M is an alkali or alkaline earth metal such as sodium, potassium, or calcium. These compounds are useful as anti-bacterials.

United States Patent Sircar et al.

[451 Oct. l4, 1975 [75] Inventors: Jagadish C. Sircar, Dover; Harold Zinnes, Rockaway; John Shave], Jr., Mendham, all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Nov. 14, 1974 [21] Appl. No.: 523,767

Related US. Application Data [62] Division of Ser. No. 464,707, April 26, 1974, Pat.

[52] US. Cl 260/239.1; 260/239.1 [51] Int. Cl. C07D 499/44 [58] Field of Search 260/239.1

[56] References Cited UNITED STATES PATENTS 3,329,675 7/1967 Album et a1 260/239.1 3,736,318 5/1973 McCaully et a1. 260/239.1

Primary ExaminerGerald A. Schwartz Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow; George M. Yahwak ABSTRACT B-Ketoacyl derivatives of 6-aminopenicillanic acid of the formula:

CNl-l S CH3 R1 so? 0 ca,

COOM

are disclosed. In the above structure R is hydrogen, alkyl, halogen, alkoxy, cyano, trifluoromethyl and the like; Z is CHR or NR R is hydrogen, alkyl, aralkyl; M is an alkali or alkaline earth metal such as sodium, potassium, or calcium. These compounds are useful as anti-bacterials.

2 Claims, No Drawings B- KETOACYL DERIVATIVES F 6-AMINOPENICILLANIC ACIDAND PROCESS THEREOF This is a division of application Ser. No. 464,707 filed Apr. 26, 1974, now US. Pat. No. 3,878,198.

The present invention relates to semisynthetic penicillins, and more particularly it relates to a-ketoacyl derivative of 6-amino-peni'cillanic acid of the formula:

v 0 ll CNH s R1 wherein R is hydrogen, alkyl, halogen, alkoxy, cyano, trifluoromethyl and the like; Z is Cl-lR or NR R is hydrogen, alkyl, aralkyl; M is an alkali or alkaline earth metal such as sodium, potassium, or calcium. Alkyl and alkoxy" as used in the specification and in the claims are meant to have 1 to 7 carbon. These include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and so on. Aralkyl encompasses alkyl as defined in which an aryl group of 6 to 10 carbon atoms is substituted for a hydrogen atom such as, for example, benzyl, phenethyl and the like.

The compounds I are useful as antibacterial agents. At concentrations of 31 to 500 mcg/ml they inhibit S. aureus and at concentrations of 67-500 meg/ml they inhibit N. gonorrhoeae.

These compounds are accordingly indicated in the treatment of infections caused by these susceptible organisms. Generally speaking the dose for treating such infections in an adult is about 500 mg to 1000 mg orally or topically.

Compound I is formulated with dosage forms for oral or topical administration utilizing known pharmaceutical technology for preparing penicillin derivatives.

According to the process of this invention, 6-aminopenicillanic acid II is reacted with an activated ester of 40 structure Ill, where R is hydrogen or N0 is the presence of a base such as triethylamine. The

0H h) COG 0:

III

initially formed triethylammonium salt is converted to the dimetal salt by treatment with a metal salt of an organic acid such as 2-ethylhexanoic acid.

The starting compound ll is commercially available.

5 The starting compounds III are prepared by the following scheme:

I? C 2 R1 u s a lcocl'a, Et,N u R o EN] E VI An enamine of structure IV is reacted with phosgene to give the acid chloride V. This is not isolated as such but is reacted with a phenol of structure VI to form an enamine ester of structure Vll. Acid hydrolysis of Vll gives the required activated ester Ill.

scribed by Zinnes, et al., J. Org, Chem. 31, 162 (1966) and in our patent application Ser. No. 251, 163 (filed 5-5-72). The compound [I] wherein R and R are hydrogen and Z is NCl-l is alsodescribed in the latter application.

In order to illustrate further the practice of this invention, the following examples are included. Temperature is given in degrees centigrade.

The preparation of the starting enamine 1V is de- Dipotassium 6-[(4-HYdroxy-2 methyl-2H-l ,2-benzothiazin-3- yl)formamido1penicillanate S,S-Dioxide.

A solution of 3.2 g (0.015 mol) I of 6- aminopenicillanic'acid arid 6.0 ml of. triethylamine in 25 ml of dichloromethane was cooled to and 5.6 g (0.015 mol) of p-nitrophenyl 4-hydroxy-2-methyl-2H- l,2-benzothiazine-3-carboxylate l,l-dioxide was added (as the solid powder) followed by 3.0 ml of additional triethylamine and 7.5 ml more dichloromethane. The reaction mixture was stirred at room temperature for 90 hr after which time the infrared spectrum of a small sample indicated that there was no further decrease in the intensity of the ester carbonyl band at l690 cm. Dilution of the reaction mixture with 100 ml of ether resulted in separation of an oil. The solvent was removed by decantation, the oil was dissolved in 25 ml of dichloromethane, and reprecipitated by the addition of 100 ml of ether. This procedure was repeated twice.-

more and the resulting oil was triturated with dry ether to give a brown solid (the triethylammonium salt) whose infrared spectrum showed bands at 1760, 1600, and 1172 cm", representing the a-lactam, amide and S0 groups, respectively. This crude salt was dissolved in 30 ml of methanol and ml of a 2.4 molar solution of potassium 2-ethylhexanoate in n-butanol was added. Dilution with 100 ml of ether resulted in precipitation of the desired potassium salt. This was redissolved in ml of methanolf'the solution was filtered, and 100 ml of dry ether was added. The resulting precipitate was redissolved in 20 ml of methanol and reprecipitated by the addition of 50 ml of dry ether. The resulting precipitate' was collected and dried in vacuo over phosphorous pentoxide at room temperature for 48 hr to give 1.6 g of product which didnot melt but started to decompose at 230.

v 3400, 1760, 1600,1172 -cm A 234 (6,400), 322 (5,600) my.

EXAMPLE 2 p-Nitrophe'nyl' 4-(' l -pyrrolidinyl )-2-H l-benzothiopyran-3- carboxylate 1,1- Dioxide.

A solution of 6.0g (0.06 mol) oflphosgene ml of benzene was diluted with 30 ml of tetrahydrofuran treated with ice-water and extracted with dichloromethane il'he dried dichlorom ethane phase was evaporated to an oilyresidue which became a gummy semisolid on trituration with several portions of ether. This gum was dissolved in dichloromethane. Slow distillation resulted in the crystallization of 13.0 g of product, mp l7 l-l 74 dec. Recrystallization from a mixture of 250ml of tetrahydrof uran and 250 ml of isopropyl ether gave 10.7 g of material, mp l75l78 dec.

Anal. Calcd for C H N- O S: C, 57.96; H, 4.38; N, 6.76; S, 7.74. Found: C, 57.90; H, 4.64;

' EXAMPLE 3 EXAMPLE 4 COOK A solution of 2.16 g (0.01 mol) of 6-amino penicillanic acid and 4ml of triethylamine in 18 ml of dichloromethane was cooled to 0 and a solution of 3.8 g (0.0105 mol) of p-nitrophenyl 4-hydroxy-2H-lbenzothiopyran-3-carboxylate l,l-dioxide and 2 ml of triethylamine in 10 ml of dichloromethane was added. The reaction mixture was stirred at 0 for one hour and then at room temperature for 20 hr after which time the infrared spectrum of a small sample indicated that the ester band at 1690 cm had nearly disappeared. Dilution with 75 ml of ether resulted in separation of an oil. The solvent was removed by decantation, the oil was dissolved in 20 ml of dichloromethane and reprecipitated by the addition of 50 ml of ether. This procedure was repeated twice more and the resulting oil was tritur'ated'with 50 ml of dry ether to give a yellow solid (thetriethylammo'nium salt) whose infrared spectrum showed bands at 1760, 1605, and l cm, representing the B-lactam, amide, and S0 groups, respectively. This crude salt was dissolved in 30 ml of methanol, ml of a 2.4 molar solution of potassium 2- ethylhexanoate in n-butanol was added, and the solution was allowed to stand for minutes. Dilution with 80 ml of anhydrous ether resulted in precipitation of the desired potassium salt, This was redissolved in ml of methanol and reprecipitated by the addition of 60 ml of ether. This dissolving and reprecipitation process was repeated, the crystalline precipitate was collected, triturated with ether, and dried in vacuo over phosphorous pentoxide at room temperature for 20 hr to give 3.0 g of product, mp 235240dec. v 3400, 1760, 1600, 1158 cm. )t f 236 (7,700), 338 (5,000)

We claim:

1. A compound of the formula:

6 no if I cuu---' s m |\2 4r-N 50g 0 CH:

coon

mamidolpenicillinate S,S,-dioxide. 

1. A COMPOUND OF THEFORMULA
 2. A compound according to claim 1 which is dipotassium 6((4-hydroxy-2H-1-benzothiopyran-3yl)formamido)penicillinate S,S,-dioxide. 